Pancreatitis annually accounts for approximately 881,000 ambulatory care visits, 454,000 hospital discharges, and more than $2.5 billion in health care costs. Recurrent acute (RAP) and chronic pancreatitis (CP) are complex, overlapping syndromes of pancreatic inflammation of common etiology but unpredictable complications, including pancreatic cancer and diabetes. The North American Pancreatitis Study 2 (NAPS2) began in 2002 as a prospective molecular epidemiology study conducted at 20 expert pancreas centers across the US. We achieved our enrollment targets of 1000 cases (RAP=460, CP=540) plus 695 controls and are on track to enroll an additional 500 CP cases by late 2010 as well as additional African American RAP and CP cases (n=250) and controls (n=250) (R01DK077906) by 2014. Epidemiological tools are implemented in a standardized fashion across all NAPS2 sites to collect phenotypic data from medical history, family history, and quantitative environmental exposure measures. We collect incident and timing data on alcohol use, smoking history, diagnosis, imaging, pathology, pain (e.g., nature, frequency, severity, duration), treatment, and quality of life (i.e., SF12). With NIDDK support to date, we have discovered an alcohol risk threshold of >5 drinks (>60 g) per day;that the majority of patients with RAP or CP are not alcoholics;that smoking is an independent risk factor for CP;and that drinking and smoking effects are additive. We also discovered a new class of cystic fibrosis transmembrane conductance regulator (CFTR) variants that alter bicarbonate but not chloride conductance, such that the pancreas is affected (but not lungs, skin, or intestines). We demonstrated strong epistasis between CFTR and serine protease inhibitor Kazal type 1 (SPINK1) variants as a model of complex traits. The key has been outstanding phenotyping by our team. We now propose to conduct a genome-wide association study (GWAS) and further expand the cohort for more power and resolution. Specifically, we will: 1) Conduct a discovery GWAS in 2000 pancreatitis patients and 2500 controls using the Human OmniExpress- 12 BeadChip (data from 1440 previously genotyped controls will also be available for analysis);2) Obtain information from two European pancreatitis cohort studies (n=2850) corresponding to the lead SNPs from our combined discovery cohort analysis (Aim 1) for replication/meta analysis;and 3) Strengthen the NAPS2 pancreatitis cohort by ascertaining additional subjects (N=700). Identifying genetic, environmental, and metabolic contributors to pancreatic pathology will better define RAP and CP as diseases, including optimal diagnostic and treatment approaches and drug discovery. The NAPS2 program represents a sound investment toward addressing several NIDDK research goals and offers an exceptional framework for training the next generation of pancreatology researchers through direct participation in ongoing studies as well as secondary analyses of the rich datasets and biospecimens available for the largest pancreatitis cohort in the US.